This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine and marijuana dependence. Many subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. The pharmacokinetic approach being studied is blunting the rate of onset of drug effect by enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE), a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Behavioral Pharmacology Section and the National Institute on Aging Gerontology Research Center, rats pretreated with BChE had a 50% reduction in motor activity response to an IP cocaine challenge compared to rats pretreated with saline. BChE itself had no effect on motor activity. BChE-treated rats had 400-fold increases in plasma and 3-fold increases in cerebrospinal fluid BChE activity 24 hours after treatment, suggesting the possibility of persisting effects from a single enzyme administration. BChE pretreatment in rats significantly decreased cocaine plasma half-life from 26.2 min to 16.4 min and increased plasma and brain levels of ecgonine methylester, a cocaine metabolite that may have protective effects. These findings suggest the important influence of BChE activity on cocaine pharmacokinetics. Pharmacodynamic approaches being studied include modulation of brain mu-opiate receptors and blockade of relevant neurotransmitter receptors. The former approach is being implemented using buprenorphine, a partial mu-opiate receptor agonist. A controlled clinical trial of sublingual buprenorphine in outpatients dependent on both cocaine and opiates found that high doses (8 mg or 16 mg daily) significantly reduced both cocaine and opiate use over the 10-week maintenance treatment period, while lower doses (2 mg daily or 16 mg every other day) did not. Attendance at concurrent drug abuse counseling was associated with better treatment outcome, suggesting the importance of combined pharmacological and psychosocial treatment. The second approach is being implemented, in collaboration with the Chemistry & Drug Metabolism Section, by evaluating the effects in humans of an experimental compound, rimonabant, which acts as an antagonist at the cannabinoid 1 (CB1, marijuana) receptor in the brain, and on its interaction with smoked marijuana. A single 90 mg dose of rimonabant significantly reduced the psychological (feeling of marijuana intoxication) and cardiovascular (tachycardia, symptomatic hypotension) effects of a marijuana cigarette. Rimonabant by itself had no measurable effects, and did not alter THC plasma pharmacokinetics. Daily rimonabant dosing for 2 weeks produced similar blockade of smoked marijuana effects. These findings suggest that CB1 receptors play an important role in mediating the effects of smoked marijuana in humans.